Platelets are small, anucleated blood cells which have a seminal role in hemostasis and thrombosis. Cardiovascular disease, the major cause of death and morbidity in developed countries, is often a result of ischemic and/or thromboembolic events including chronic unstable angina transient ischemic attacks and strokes, myocardial infarction, chronic unstable angina, peripheral vascular disease, coronary thrombosis, restenosis and/or thrombosis following angioplasty and others. These events represent various stenotic and occlusive vascular disorders involving platelet aggregation on vessel walls or within the lumen. In: Platelets, Alan D. Michelson (ed.) Academic Press, (2002)(incorporated herein by reference).
Antibodies have been considered as clinically significant therapeutic agents for various platelet-mediated cardiovascular disorders. However, antibody therapy poses serious disadvantages. First, as antibodies are natural products they must be produced in cell lines or other live expression systems. This raises a that there could be contamination of antibody preparations by infectious agents such as prions or viruses. Although tight regulation and regulatory vigilance and surveillance can reduce this concern, the need for ongoing monitoring and testing for contamination contributes to the high cost of developing and administering antibody therapies. In addition, antibody-based therapies require considerable logistical support. As antibodies are proteins, they cannot be given orally, except for those used to treat certain types of mucosal infectious diseases, and therefore, systemic administration is required. Another serious disadvantage of antibody-based therapies is the high costs of production, storage, and administration. Moreover, long infusions (i.e., for example, an hour or longer) require a hospital environment and are often associated with mild to very severe side effects. For example, in one trial, in which four patients in the U.K. were given an anticancer antibody reactive against an important T-cell receptor (CD28) severe and life-threatening responses were observed; the cause is at present not understood. This makes large-scale clinical applications of a number of monoclonal antibodies with demonstrated therapeutic activity impossible or, at least, severely compromised. Fast degradation of the administered antibodies is another drawback of antibody-based therapy.
What is needed in the art is a broad-based therapy designed to disrupt protein-protein interactions that may be administered to treat various cardiovascular diseases having an underlying platelet etiology that is safe and effective.